Updated WHO Classification of Hematological … · Acute Lymphoblastic Leukemia •B-cell lymphoblastic leukemia/lymphoma (B-ALL) –B-ALL with intrachromosomal amplification of chromosome

Updated WHO Classification of Hematological

Neoplasms:

Acute Leukemias and Myelodysplastic Syndromes

Daniel A. Arber, MD

Stanford, California

Overview

• Acute lymphoblastic leukemia

• Acute myeloid leukemia

• Myelodysplastic syndromes

• Myeloid neoplasms with germline predisposition

Arber DA, et al. Blood 127;2391, 2016

Acute Lymphoblastic Leukemia

• B-cell lymphoblastic leukemia/lymphoma (B-ALL) – B-ALL with intrachromosomal amplification of

chromosome 21 (iAMP21)

– B-ALL with translocations involving tyrosine kinases or cytokine receptors (BCR-ABL1-like ALL)

– Association between low hypodiploid ALL and often constitutional mutations in TP53

• T-cell lymphoblastic leukemia/lymphoma (T-ALL) – Indolent T-lymphoblastic proliferations

– Early T-precursor (ETP) ALL

• Intrachromosomal amplification of chromosome 21 (iAMP21) accounts for about 2% of pediatric B-ALL

• Generally in older children (median age 9 years) with lower WBC count

• Uncommon in adults • Adverse outcomes when treated with

standard risk therapy; but improved when treated as high risk ALL

• Presence of 5 or more copies of RUNX1 on a single cell or 3 or more extra copies on a single abnormal chromosome 21 in metaphase FISH

• Reliably detected by FISH for RUNX1 used to evaluate for B-ALL with ETV6-RUNX1

Image provided by Dana Bangs

B-ALL with iAMP21

Harrison et al. Leukemia 28:1015, 2014

• BCR-ABL1-like B-ALL is a high risk ALL with a gene expression profile similar to that of BCR-ABL1+ ALL

• Accounts for 10% of pediatric and 25% of adult ALL; poor clinical outcomes; some cases respond to TKI therapy

• Need to establish clear diagnostic criteria • CRLF2 translocations

• Usually show increased expression of CRLF2 by flow cytometry analysis

• Some have activating mutations or translocations of genes, such as ABL1, ABL2, JAK2, PDGFRB, NTRK3, TYK2, CSF1R, and/or EPOR • Diagnostic significance of

deletions/mutations of IKZF1, CDKN2A/B, JAK1 less clear

• The full spectrum of genetic changes is still being investigated

BCR-ABL1-like B-ALL (B-ALL with Translocations Involving Tyrosine Kinases or Cytokine

Receptors)

van der Veer et al. Blood 122:2622, 2013 Izraeli. Curr Opin Hematol 21:289, 2014

• Early T-Precursor (ETP) ALL comprises 10-15% of T-ALL • Defined immunophenotypically by expression of CD7,

but not CD1a or CD8 • Express one or more of the following CD34, CD117, HLA-

DR, CD11b, CD65, CD33, or CD13, but not MPO • Usually express CD2 and cCD3; CD5 negative or absent in

25% or more of cells

• Thought to arise from an early progenitor cell with lineage plasticity that may be more closely related to human stem cells than to early T-cell precursors

• Molecular genetics • Increase in AML-associated mutations (FLT3, NRAS/KRAS,

DNMT3A, IDH1, IDH2) • Infrequent NOTCH pathway (T-ALL-associated) mutations

• Initially considered high risk due to higher rate of induction failure

• Recent COG study suggests no outcome difference with current T-ALL therapy

Early T-Precursor Acute Lymphoblastic Leukemia (ETP-ALL)

• Coustan-Smith E, et al. Lancet Oncol 10:147, 2009

• Haydu JE and Ferrando AA. Curr Opin Hematol 20:369, 2013

• Wood BL, et al. Blood 124:1, 2014

2016 WHO Classification of Lymphoblastic Leukemia/Lymphoma

B lymphoblastic leukemia/lymphoma

B lymphoblastic leukemia/lymphoma, NOS

B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities

B lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1

B lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged

B lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1

B lymphoblastic leukemia/lymphoma with hyperdiploidy

B lymphoblastic leukemia/lymphoma with hypodiploidy

B lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH

B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1

Provisional entity: B lymphoblastic leukemia/lymphoma, BCR-ABL1-like

Provisional entity: B lymphoblastic leukemia/lymphoma with iAMP21

T lymphoblastic leukemia/lymphoma

Provisional entity: Early T-cell precursor lymphoblastic leukemia

Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma


Acute Myeloid Leukemia

• AML with recurrent genetic abnormalities

• AML with myelodysplasia-related changes

• Therapy-related myeloid neoplasms

• AML, not otherwise specified

• Myeloid sarcoma

• Myeloid proliferations related to Down syndrome

• Blastic plasmacytoid dendritic cell neoplasm

AML with Recurrent Genetic Abnormalities

Cytogenetic groups

• Minor changes – APL with PML-RARA

– AML with t(9;11)(p21.3;q23.3); KMT2A-MLLT3

– AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

• New provisional entity

– AML with BCR-ABL1

AML with BCR-ABL1

• Difficult to distinguish from myeloid blast crisis of chronic myeloid leukemia

• Deletion of antigen receptors (IGH, TCR), IKZF1 and/or CDKN2A may support a diagnosis of de novo disease

• Patients may benefit from targeted (TKI) therapy

• New provisional entity Soupir CP, et al. Am J Clin Pathol 127:642, 2007 Konoplev S, et al. Leuk Lymphoma 54:138, 2013 Nacheva EP, et al. Br J Haematol 161:541, 2013


Mutations

• Revised categories

– AML with mutated NPM1

– AML with biallelic mutations of CEBPA

• New provisional entity

– AML with mutated RUNX1

AML with mutated CEBPA

• 7-20% of AMLs have mutations of CEBPA – More frequent with normal

or intermediate karyotype

• 12.5-47% are single/monoallelic

• Double mutant/biallelic cases (CEBPAdm) predict a favorable prognosis – Low frequency of other

mutations or other cytogenetic abnormalities

Green CL, et al. J Clin Oncol 28:2739, 2010

NPM1 and CEBPA Mutations and Multilineage Dyplasia

• Significance of multilineage dysplasia in the presence of NPM1 mutation, a normal karyotype and no history of MDS – MLD found in 74/318 (23%) de

novo NPM1 mutated AML

– No prognostic significance for MLD

• CEBPA mutations

– MLD found in 28/108 (25.9%) CEPBA mutated AML patients

– No significant survival difference in MLD+ and MLD- groups

Falini et al. Blood 115:3776, 2010 Díaz-Beyá M et al. Blood 116:6147, 2010 Bacher U et al. Blood 119:4719, 2012

Survival curves of patients up to 60 years with intermediate-risk cytogenetics AML depending on NPM1 status and presence of

multilineage dysplastic features (MLD)

Díaz-Beyá M et al. Blood 2010;116:6147-6148

©2010 by American Society of Hematology


Revisions

– AML with mutated NPM1 and AML with biallelic mutations of CEBPA no longer provisional entities

– Biallelic mutations required for CEBPA category

– Multilineage dysplasia alone no longer trumps these mutations

AML with mutated RUNX1

• Gene located at 21q22 • Encodes the alpha subunit of the

core binding factor • Mutation in 12.5-13.2% of AML • More frequent in older male patients • Frequent prior history of MDS, or

prior exposure to radiation • Frequent among FAB M0 cases, but

wide morphologic spectrum • Frequently associated KMT2A-PTD,

IDH1/2 or ASXL1 mutations • Rare CEBPA or NPM1 mutations • Poor response to therapy with

shortened survival • Germline mutations should be

evaluated

Tang et al. Blood 114:5352, 2009 Mendler et al. J Clin Oncol 30:3109, 2012

AML with mutated RUNX1

• Provisional entity

– Only includes de novo cases without MDS-related cytogenetic abnormalities

– Does not include therapy-related cases

2016 WHO Classification of AML with Recurrent Genetic Abnormalities

AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11

APL with PML-RARA

AML with t(9;11)(p21.3;q23.3); KMT2A-MLLT3

AML with t(6;9)(p23;q34.1); DEK-NUP214

AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1

Provisional entity: AML with BCR-ABL1

AML with mutated NPM1

AML with biallelic mutations of CEBPA

Provisional entity: AML with mutated RUNX1


AML with Myelodysplasia-Related Changes

• Multilineage dysplasia alone no longer trumps a diagnosis of AML with mutated NPM1 or AML with biallelic mutations of CEBPA

• Changes to the MDS-related cytogenetic abnormality table

AML with mutated NPM1 or CEBPA and an abnormal karyotype

• Abnormal karyotype identified in 14.7% of NPM1 mutated AML cases

• +8, +4, -Y, del(9q) and +21 most frequent

• del(9q) is currently considered an MDS-related cytogenetic abnormality, but it appears to be unusually common in NPM1 and CEBPA mutated cases

• Not clear if del(9q) has prognostic significance in this setting

• MDS-related cytogenetic abnormality list to diagnose AML with myelodysplasia-related changes is now changed to not include del(9q)

Haferlach C, et al. Blood 114:3024, 2009 Schlenk RF, et al. Blood 122:1576, 2013

MDS-related cytogenetic abnormalities

• Complex karyotype*

• Unbalanced abnormalities – -7/del(7q)

– -5/del(5q)/t(5q)

– i(17q)/t(17p)

– -13/del(13q)

– del(11q)

– del(12p)/t(12p)

– del(9q)

– idic(X)(q13)

• Balanced abnormalities – t(11;16)(q23.3;p13.3)

– t(3;21)(q26.2;q22.1)

– t(1;3)(p36.3;q21.1.2)

– t(2;11)(p21;q23.3)

– t(5;12)(q32;p13.2)

– t(5;7)(q32;q11.2)

– t(5;17)(q32;p13.2)

– t(5;10)(q32;q21)

– t(3;5)(q25.3;q35.1)

*>3 abnormalities

AML with Myelodysplasia-Related Changes

• Detection of multilineage dysplasia

– Two non-blast cell lines must show dysplasia in at least 50% of cells

• MDS-related cytogenetic abnormalities, or

• History of MDS or MDS/MPN

• Absence of the specific cytogenetic abnormalities of AML with recurrent genetic abnormalities

• Absence of prior history of therapy

AML, Not Otherwise Specified

• Elimination of the category of erythroid/myeloid type of acute erythroid leukemia

• Eliminates the use of non-erythroid cell blast counts for classification

AML, Not Otherwise Specified

AML with minimal differentiation

AML without maturation

AML with maturation

Acute myelomonocytic leukemia

Acute monoblastic/monocytic leukemia

Pure erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis


Myelodysplastic Syndrome Changes

• Nomenclature

• Morphology

– MDS, unclassifiable

• Genetics and molecular genetics

– MDS with ring sideroblasts

– MDS with isolated del(5q)

Arber DA, Hasserjian RP. Hematology Am Soc Hematol Educ Program 2015(1):294-298.

Cazzola M et al. Blood 2013;122:4021-4034

Nomenclature

• WHO scheme classifies based on dysplasia and blast counts, not cytopenia – Cytopenias are captured in IPSS-R system

• Type of dysplasia often does not agree with the cytopenic lineage in refractory cytopenia with unilineage dysplasia (RCUD) – Cannot predict peripheral counts from dysplasia

– Subgroups of refractory anemia, neutropenia, and thrombocytopenia will be eliminated

Verburgh E et al. Leukemia 2007;21:668, Germing U et al. Leuk Res 2012;36:727, Maasen A et al. Leuk Res 2013;37:64

Myelodysplastic Syndromes – Revised Terminology

• Refractory cytopenia with unilineage dysplasia – Refractory anemia – Refractory neutropenia – Refractory thrombocytopenia

• Refractory anemia with ring sideroblasts

• Refractory cytopenia with multilineage dysplasia

• Refractory anemia with excess blasts – RAEB-1 – RAEB-2

• Myelodysplastic syndrome with isolated del(5q)

• Myelodysplastic syndrome, unclassifiable

• Childhood myelodysplastic syndrome – Refractory cytopenia of childhood

• MDS with single lineage dysplasia • MDS with ring sideroblasts and single

lineage dysplasia • MDS with ring sideroblasts and

multilineage dysplasia • MDS with multilineage dysplasia • MDS with excess blasts

– With excess blasts-1 – With excess blasts-2

• MDS with isolated del(5q)

• MDS, unclassifiable • Refractory cytopenia of childhood

MDS, Unclassifiable

• Findings of MDS with single lineage dysplasia or multilineage dysplasia (<5% marrow blasts), but 1% peripheral blood blasts – 1% PB blasts must be measured on at least two separate

occasions

• Findings of MDS with single lineage dysplasia, but pancytopenia – Cytopenias must be below IPSS levels: ANC<1.8 x 109/L,

HGB<10 g/dL, PLT<100 x 109/L

• MDS-associated cytogenetic abnormality in association with cytopenias, less than 1% blood and less than 5% marrow blasts, but less than 10% dysplasia in any cell line

Genetics in MDS

• Somatic mutations in MDS – Prognostic significance

of mutations of TP53, EZH2, ETV6, RUNX1, ASXL1 and others (Bejar R et al. NEJM 2011;364:2496)

• SF3B1 mutations in MDS with ring sideroblasts

• MDS with isolated del(5q)

Ribosomal proteins: RPS14 Epigenetic regulators: TET2, ASXL1 RNA splicing: SF3B1, SRSF2, U2AF1 Transcription factors: RUNX1, ETV6 Tyrosine kinase signaling: RAS Tumor suppressor genes: TP53

Papaemmanuil E et al. Blood. 2013;122:3616

MDS with ring sideroblasts (with single lineage or multilineage dysplasia)

• Frequent association with mutations of SF3B1 and a favorable prognosis with low risk of transformation to acute leukemia

• WHO revision: – >15% ring sideroblasts (among

erythroid precursors), or – >5% in the presence of an SF3B1

mutation – Blast cell increases exclude this

diagnosis • If multilineage dysplasia without a

blast cell increase is present, case is classified as MDS with ring sideroblasts and multilineage dysplasia

Papaemmanuil E NEJM 2011;365:1384, Patniak MM Blood 2012;119:5674, Bejar R JCO 2012;30:3376, Malcovati L Blood 2011;118:6239, Malcovati L Blood 2015;126:233, Woll PS Cancer Cell 2014;25:794

MDS with Isolated del(5q) (5q-minus Syndrome)

• 2008 WHO restricted category to allow del(5q) as the only abnormality

• Revision now allows a second (except monosomy 7) cytogenetic abnormality

• Cases with >2 abnormalities will not qualify for this category

• Recommend TP53 mutation assessment or p53 staining

Germing Leukemia 26:1286, 2012; Mallo Leukemia24:110, 2011; Jadersten JCO 29:1971; 2011

MDS with Isolated del(5q) (5q-minus Syndrome)

• 2008 WHO restricted category to allow del(5q) as the only abnormality

• Revision now allows a second (except monosomy 7) cytogenetic abnormality

• Cases with >2 abnormalities will not qualify for this category

• Recommend TP53 mutation assessment or p53 staining

Germing Leukemia 26:1286, 2012; Mallo Leukemia24:110, 2011; Jadersten JCO 29:1971; 2011

Acute erythroid leukemia (erythroid/myeloid type) is now MDS based on total blast count

• 2008 definition of acute erythroleukemia (erythroid/myeloid type) in AML, NOS required >50% marrow erythroid precursors and >20% myeloblasts among non-erythroid cells

• These cases will now be classified as MDS based on the total blast cell count

Grossman et al. Leukemia 27:1940, 2013 Hasserjian et al. Blood 115:1985, 2010 Wang et al. Mod Pathol 2015 abstract

Diagnostic approach to myeloid neoplasms when erythroid precursors comprise ≥50% of bone marrow

(BM) nucleated cells

BM erythroid precursors

Myeloblast % of all cells in BM (or PB)

Prior Therapy?

Recurring WHO genetic abnormality?

Meets criteria for AML-MRC?

4th edition diagnosis (2008)

Updated 4th edition diagnosis (2016)

≥50% NA Yes NA NA Therapy-related myeloid neoplasm

Therapy-related myeloid neoplasm

≥50% ≥20% No Yes NA AML with recurring genetic abnormality

AML with recurring genetic abnormality

≥50% ≥20% No No Yes AML with myelodysplasia-related changes

AML with myelodysplasia-related changes

≥50% ≥20% No No No AML, NOS, acute erythroid leukemia (erythroid/myeloid type)

AML, NOS (non erythroid subtype)

≥50% <20%, but ≥20% of non-erythroid cells

No No* NA AML, NOS, acute erythroid leukemia (erythroid/myeloid subtype)

MDS**

≥50% <20%, and <20% of non-erythroid cells

No No* NA MDS** MDS**

>80% immature erythroid precursors with >30% proerythroblasts

<20% No No* NA AML, NOS, acute erythroid leukemia (pure erythroid type)

AML, NOS, acute erythroid leukemia (pure erythroid type)

* Cases of AML t(8;21)(q22;q22.1); RUNX1-RUNX1T1, AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 or acute promyelocytic leukemia with PML-RARA, may rarely occur in this setting with less than 20% blasts and those diagnoses would take precedence over a diagnosis of AML, NOS or MDS. ** Classify based on myeloblast percentage of all BM cells and of peripheral blood leukocytes and other MDS criteria Abbreviations: BM, bone marrow; PB, peripheral blood; AML, acute myeloid leukemia; AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; AML-NOS, acute myeloid leukemia, not otherwise specified; NA, not applicable; MDS, myelodysplastic syndrome Arber DA, et al. Blood 127;2391, 2016

Myelodysplastic Syndromes

MDS with single lineage dysplasia MDS with ring sideroblasts MDS with ring sideroblasts and single lineage dysplasia MDS with ring sideroblasts and multilineage dysplasia MDS with multilineage dysplasia MDS with excess blasts MDS with isolated del(5q) MDS, unclassifiable Provisional entity: Refractory cytopenia of childhood


Myeloid Neoplasms with Germline Predisposition

Myeloid neoplasms with germline predisposition are likely more prevalent than realized Myeloid neoplasms with germline predisposition without a pre-existing disorder or organ dysfunction AML with germline CEBPA mutation Myeloid neoplasms with germline DDX41 mutation* Myeloid neoplasms with germline predisposition and pre-existing platelet disorders Myeloid neoplasms with germline RUNX1 mutation* Myeloid neoplasms with germline ANKRD26 mutation* Myeloid neoplasms with germline ETV6 mutation* Myeloid neoplasms with germline predisposition and other organ dysfunction Myeloid neoplasms with germline GATA2 mutation Myeloid neoplasms associated with bone marrow failure syndromes Myeloid neoplasms associated with telomere biology disorders Juvenile myelomonocytic leukemia associated with neurofibromatosis, Noonan syndrome or Noonan syndrome-like disorders Myeloid neoplasms associated with Down syndrome* * Lymphoid neoplasms also reported.

West AH, Godley LA & Churpek JE. Ann NY Acad Sci 1310:111, 2014 Zhang MY, et al. Nature Genetics 47:180, 2015

Summary

• The 2016 revision of the WHO classification clarifies the diagnostic criteria for some existing neoplasms and introduces some new categories as provisional entities

• The classification recognizes the prognostic significance of many genetic changes, especially mutations, even if they do not directly impact diagnostic categories

Acknowledgements

• Jim Vardiman • Jürgen Thiele • Attilio Orazi • Robert Hasserjian • Kathy Foucar • LoAnn Peterson • Dick Brunning • Michelle LeBeau • Mike Borowitz • Myeloid CAC

– Clara Bloomfield – Mario Cazzola

Documents

Updated WHO Classification of Hematological … · Acute Lymphoblastic Leukemia •B-cell lymphoblastic leukemia/lymphoma (B-ALL) –B-ALL with intrachromosomal amplification of chromosome